US7186988B2 - Method for analyzing chemical and or biological samples - Google Patents

Method for analyzing chemical and or biological samples Download PDF

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Publication number
US7186988B2
US7186988B2 US10/471,042 US47104204A US7186988B2 US 7186988 B2 US7186988 B2 US 7186988B2 US 47104204 A US47104204 A US 47104204A US 7186988 B2 US7186988 B2 US 7186988B2
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observation
deflection mirror
microscope
mirror
sample
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US10/471,042
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US20040238729A1 (en
Inventor
Jürgen Müller
Stefan Hummel
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Evotec OAI AG
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Evotec OAI AG
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6456—Spatial resolved fluorescence measurements; Imaging
    • G01N21/6458—Fluorescence microscopy
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6452—Individual samples arranged in a regular 2D-array, e.g. multiwell plates
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0004—Microscopes specially adapted for specific applications
    • G02B21/002—Scanning microscopes
    • G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0004—Microscopes specially adapted for specific applications
    • G02B21/002—Scanning microscopes
    • G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
    • G02B21/0036—Scanning details, e.g. scanning stages
    • G02B21/0048—Scanning details, e.g. scanning stages scanning mirrors, e.g. rotating or galvanomirrors, MEMS mirrors
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0004—Microscopes specially adapted for specific applications
    • G02B21/002—Scanning microscopes
    • G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
    • G02B21/0052—Optical details of the image generation
    • G02B21/0076—Optical details of the image generation arrangements using fluorescence or luminescence

Definitions

  • the invention relates to a method for analyzing chemical and/or biological samples, particularly in high- and medium throughput screening. Further, the invention relates to a microscope for performing said method, as used particularly in fluorescence spectroscopy.
  • Microscopes serve for the optical coverage of the processes taking place in an observation volume.
  • Known confocal microscopes comprise an illumination unit, e.g. a laser, for generating an observation beam, particularly in the form of exciting light.
  • the exciting light optionally after conditioning by a lens arrangement, is incident onto a dichroic mirror which will reflect the light in the direction of the observation volume. Thereafter, the light is directed to pass through a lens system, particularly a microscope objective, which will focus the light in the observation volume.
  • a lens system particularly a microscope objective
  • the observation volume which includes e.g. biological and/or chemical samples, e.g. fluorescence is generated by the exciting light depending on the respective composition of the samples.
  • the thus generated fluorescent light passes (through the microscope objective and through the dichroic mirror to a detector unit.
  • An aperture stop can be provided before the detector unit, with the fluorescent light focused into the aperture stop; thus, a confocal microscope is obtained.
  • a known approach for moving the light beam resides in the provision of one or a plurality of mirrors in the beam path of the microscope, which mirrors can be tilted back and forth by means of a drive mechanism.
  • the provision of two mirrors offers the possibility to move the light beam within a plane of the observation volume. Arrangements of this type have the disadvantage that the tilting movement of the mirror has a dead center so that the movement of the light beam will be decelerated and accelerated. This causes a non-uniform excitation of the universe within the sample and will thus impair the measurement results.
  • microscopes with tiltable mirrors entail the disadvantage that the light beam passes through the objective at different angles relative to the optical axis of the microscope objective. This causes an optical error which varies in dependence of the inclination of the tilt angle and likewise has a negative influence on the measurement results. Further, the focus of a light beam directed obliquely through the microscope objective will assume an oval shape. Thus, also the shape of the focus will change in dependence of the orientation of the tilting mirror. Thereby, too, the measurement results are adversely affected.
  • the movement of the observation beam is performed substantially continuously.
  • the movement of the observation beam or the exciting light in the observation volume of the sample is thus carried out without a reversal of directions which would lead to a considerable deceleration and acceleration of the movement of the light beam.
  • the above uniformization of the movement of the light beam in the observation volume will make the excitation highly uniform. In this manner, for instance, destruction of fluorescence markers by increased excitation is prevented.
  • the uniformity of the movement of the observation beam through the observation volume the quality of the measurement results can be considerably improved.
  • a further advantage of the inventive method resides in that a constant or uniform movement of the observation beam through the sample allows for a better realization of the fluctuation times of individual particles such as e.g. molecules (FIMDA measurements). This is made possible since, when determining the fluctuation times, consideration has to be given to the moving speed of the observation beam. In this regard, a constant or nearly constant speed of the observation beam is much more easily considered. Further, the observation times per particle are rendered uniform. This means e.g. that of each particle the same number of information items is detected. Thereby, the statistic quality of the data is considerably improved.
  • FIMDA measurements fluctuation times of individual particles such as e.g. molecules
  • the observation beam can be a beam generated by an illuminating device such as e.g. a laser; by the inventive method, this beam is caused to carry out a uniform movement in the sample.
  • the observation beam in this case will comprise e.g. exciting light.
  • the observation beam can also be the beam path of the observation. The beam path in this case extends in reverse direction. In this case, the region observed by the detector is moved in the sample.
  • what is observed is e.g. the fluorescence of a sample, i.e. the radiation emitted from the sample.
  • the movement of the observation beam is unidirectional. A reversal of the direction of movement is thus avoided.
  • massive variations within the illumination volume of the generated or observed quantity of photons i.e. variations on different illumination or observation sites, are avoided.
  • the quantity of photons in the present context is defined as the number of the generated or emitted photons per site.
  • the quantity of photons is the intensity integrated over time.
  • the dwell period of the beam at each site of the sample is constant or undergoes deviations within considerably tighter limits than in known methods. Thereby, the quality of the measurement results can be considerably improved.
  • the illumination beam is moved along a path closed in itself, preferably along an elliptic path, and still more preferably along a substantially circular path.
  • the observation beam In performing the movement of the observation beam in the observation volume, it is particularly preferred to use a deflection mirror which is rotatable about an axis of rotation.
  • the axis of rotation includes an angle ⁇ 90° together with the area of the deflection mirror.
  • the moving speed of the observation beam in the observation volume is not constant.
  • the observation beam has a lower speed. Therefore, according to the invention, it is particularly preferred to make the dwell period of the observation beam uniform by varying the rotational speed of the deflection mirror. This means that the rotational speed is set in such a manner that the observation beam in the observation volume has a speed which is deviating at the most within narrow limits. Preferably, the speed is substantially constant.
  • the uniformization of the illumination intensity acting on different illumination sites in the sample and varying particularly in dependence of the dwell period, i.e. of the moving speed of the observation beam or the exciting beam is effected by controlling the intensity of the observation beam in dependence of the moving speed.
  • the photon quantity generated by the observation beam is made uniform by speed-dependent control of the illumination intensity.
  • the intensity of the observation beam will thus be reduced when the observation beam is moving at a relatively slow speed in the observation volume.
  • a uniformization of the measurement results can be effected.
  • an impairment of the measurement results due to non-uniform excitation or a destruction of the fluorescence markers are avoided.
  • the control of the intensity of the observation beam which can be performed e.g. by time-dependent modulation of a laser, is an invention in its own right which is independent from the continuous movement of the observation beam.
  • a uniformization of the illumination intensity can be obtained by corresponding control of the intensity of the illumination beam.
  • the varying of the intensity of the illumination beam can be realized in a considerably simpler manner in case of small adjustments than in case of large deviations.
  • the adapting of the illumination intensity can also be performed e.g. by filters to be adapted to the shape of the path.
  • the microscope comprises a deflection mirror arranged to deflect an observation beam, e.g. excitation light, generated by an illumination unit.
  • an observation beam e.g. excitation light
  • the deflection mirror performs a tumble movement.
  • the tumble movement the focus is moved along a closed path in the observation volume.
  • the movement will thus be continuous.
  • a complete braking and subsequent acceleration of the light beam as occurring in tiltable mirrors will thus not take place in a mirror arranged for tumble movements.
  • the inventive configuration of the microscope can be realized at considerably lower cost than the provision of tiltable mirrors or so-called galvo scanners which require complex drive and control electronics.
  • the inventive apparatus is adapted to realize a continuous movement of the light beam on a path and to avoid strong braking and accelerating movements, higher scanning speeds are possible as compared to those obtained when using tiltable mirrors.
  • tiltable mirrors particular consideration has to be given to the large mass moment of inertia of the mirrors which prevents fast movements of the mirror. Further, fast movements of the mirrors may give rise to vibrations which will impair the measurements.
  • the inventive microscope can be used to perform the above method merely for observation of the sample.
  • a beam generated by an illumination unit is caused to perform a tumble movement.
  • the tumble mirror or another suitable device is employed to cause the site observed by an observation detector to be moved in the sample.
  • the tumble movement can be performed e.g. by a three-point suspension at the rear of the mirror.
  • the mirror can be caused to perform tumble movements.
  • the mirror is rotated about an axis of rotation.
  • the deflection mirror and the axis of rotation include an angle unequal to 90°. Alone by the rotation of the mirror, a tumble movement and thus a corresponding movement of the light beam in the observation volume will be generated.
  • the angle of the deflection mirror relative to the axis of rotation is in the range of 90.1°–95°, preferably 90.1°–92°, still more preferably 90.1°–91°.
  • a circular movement is effected preferably in that the beam path is arranged in parallel to the axis of rotation.
  • the observation beam will perform an elliptic movement in the sample or the observation volume.
  • the observation beam is moved in such a manner that the focus in the observation volume will be moved along a closed path.
  • the tumble movement in dependence of the surface of the mirror and the reflection point of the light beam on the mirror relative to the center of the tumble movement.
  • good measurement results can be obtained by having the excitation light impinge on the deflection mirror substantially in the rotational center of the mirror.
  • Such an arrangement has the advantage that the light beam will pass the measurement objective always at the same distance to the central axis of the measurement objective.
  • the deterioration of the focus relative to a light beam passing the objective in the axis of the objective is substantially constant and thus can be compensated for in a well-aimed manner by corresponding adjustment.
  • no change of the focus in dependence of the position of the mirror or the position of the focus in the sample is brought about, considerably improved measurement results can be obtained.
  • the angle of the mirror is adjustable relative to the axis of rotation or relative to a light beam incident on the deflection mirror.
  • an adjustment unit for automatic adjustment of the angle of the deflection mirror e.g. also during the examination of a sample the angle of the deflection mirror and thus the path of the focus in the sample can be varied.
  • the radius of the circular movement of the focus or the main axes of the ellipse in the sample can be changed by adjusting the above angle. In this manner, a complete scanning of the sample in a plane can be realized.
  • a further possibility for a complete scanning of the sample in a plane resides in that the angle of the deflection mirror is kept constant during the examination so that the focus will move on an unchanged path.
  • the platform holding the sample under examination will now be moved as well.
  • the movement of the platform can be one- or two-dimensional. Further, if the confocal principle is used, it is possible to combine the two above methods for scanning a sample particularly in a plane.
  • the existing dichroic mirror serving as beam splitter can be configured for use as a deflection mirror which is adapted to perform a suitable tumble movement.
  • the dichroic mirror is preferably supported in a connecting link guide.
  • the rotation is imparted from outside so that the beam path will not be affected.
  • the detector used in this embodiment is preferably an area sensor, e.g. a large-surfaced photodiode.
  • the detector area can be read in an integrated manner by means of a large-surfaced photodetector because the light incident on the detector will generate the same signal irrespective of the side where it impinges on the detector.
  • the above described microscope is a confocal microscope.
  • the measurement results can be considerably improved by use of the inventive deflection mirror.
  • a further embodiment of the invention relates to a deflection unit for a microscope for optical coverage of an observation volume.
  • the deflection unit comprises a deflection mirror connected to a drive unit and adapted to perform a tumble movement through the drive unit.
  • the deflection unit is an additional component which can be connected to a conventional microscope.
  • the deflection unit comprises a casing supporting the drive unit and/or the deflection mirror.
  • the casing comprises a connection element for connection to an objective receiving portion of a microscope, and a receiving element for receiving a microscope objective.
  • a conventional microscope can be conveniently retrofitted with the deflection unit to obtain the inventive microscope with tumbling mirror.
  • the deflection mirror provided in the inventive deflection unit can comprise the above described modifications.
  • the above described deflection unit is particularly suited for use in a confocal microscope.
  • FIG. 1 is a schematic view of a confocal microscope comprising a deflection mirror to be rotated as provided by the invention
  • FIG. 2 is a partially sectional schematic side view of a deflection unit according to the invention.
  • FIG. 3 is a plan view in the direction of the arrow III in FIG. 2 , of the microscope objective shown in FIG. 2 .
  • the confocal microscope schematically illustrated in FIG. 1 comprises an illumination device 10 provided as a laser.
  • the excitation light 12 generated by the laser is directed to a beam splitter 16 by means of a lens arrangement 14 .
  • Beam splitter 16 guides the excitation light towards a reflection mirror 18 .
  • the latter reflects the excitation light back towards a deflection mirror 20 which will reflect the excitation light towards a microscope objective 22 .
  • Microscope objective 22 is arranged to focus the excitation light 12 back into an observation volume 24 .
  • the observation volume 24 is provided as a deepened portion of a titration plate 26 whose openings 28 are closed by a glass bottom 30 .
  • the light emitted by the sample arranged in the deepened portion 28 is guided in the reverse direction through the microscope objective and is reflected by deflection mirror 20 and reflection mirror 18 towards beam splitter 16 .
  • the beam splitter 16 By means of the beam splitter 16 , the light coming from the observation volume 24 is deflected towards a tube lens 32 .
  • Tube lens 32 will focus the light in an opening 34 of an aperture stop 36 . Thereafter, the light is incident on a detector unit 38 .
  • the reflection mirror 18 is arranged at an angle of 45° relative to the exciting light 12 . In this manner, a deflection of the exciting light 12 from the usual beam path is effected.
  • This has the advantage that a drive unit for the deflection mirror 20 can be simply arranged outside the beam path. Further, the customary configuration of the confocal microscope arranged to have a sample illuminated from below, is maintained.
  • Deflection mirror 20 performs a tumble movement by being rotatable about an axis of rotation 40 in the direction of an arrow 42 .
  • the mirror 20 together with the axis of rotation includes an angle ⁇ unequal to 90°.
  • This angle ⁇ is the larger one of the two angles between the axis of rotation 40 and the mirror 20 .
  • the angle of incidence of the exciting light 12 coming from reflection mirror 18 will be changed depending on the rotational position of deflection mirror 20 .
  • the focus 44 in observation volume 24 will move in the linear direction as indicated by arrow 46 .
  • focus 44 moves on a closed path configured as an ellipse. If the exciting light impinges on the deflection mirror 20 substantially in the center of rotation 48 , the circular movement is concentric with the beam axis.
  • the deflection unit illustrated in FIGS. 2 and 3 is provided as an add-on part for a conventional confocal microscope.
  • the deflection unit has a casing 50 .
  • Casing 50 is provided with a connection element 52 .
  • This element can be e.g. a clamping means.
  • the deflection unit can be connected to an objective receiving portion of the usual type.
  • the connection element is connected with the receiving portion normally serving for receiving the microscope objective 22 .
  • the microscope objective 22 is unscrewed from the corresponding support portion, and the deflection unit is screwed into the corresponding receiving portion of the confocal microscope by means of the connection element 52 , and, if required, by use of an added adapter.
  • a reflection mirror 18 is provided Internally of the casing, a reflection mirror 18 is provided at an angle of substantially 45° relative to the exciting light 12 .
  • reflection mirror 18 is a prism.
  • the mirror 20 is arranged in a cavity 56 of casing 50 .
  • Mirror 20 is arranged at an angle to the axis of rotation 40 corresponding to mirror 20 illustrated in FIG. 1 .
  • a drive unit 58 such as e.g. an electric motor is provided for driving the deflection mirror 20 in a rotational movement.
  • the beam of the exciting light 12 is deflected as indicated by the interrupted lines 60 in the microscope objective 22 .
  • the exciting light is moved along an ellipse 62 .

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  • Physics & Mathematics (AREA)
  • General Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Optics & Photonics (AREA)
  • Immunology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Pathology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Microscoopes, Condenser (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
  • Analysing Materials By The Use Of Radiation (AREA)
  • Steroid Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
US10/471,042 2001-03-06 2002-03-05 Method for analyzing chemical and or biological samples Expired - Lifetime US7186988B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10110594.0 2001-03-06
DE10110594 2001-03-06
PCT/EP2002/002372 WO2002071043A1 (de) 2001-03-06 2002-03-05 Verfahren zur untersuchung chemischer und/oder biologischer proben

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US20040238729A1 US20040238729A1 (en) 2004-12-02
US7186988B2 true US7186988B2 (en) 2007-03-06

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US (1) US7186988B2 (da)
EP (1) EP1366352B1 (da)
JP (1) JP4391746B2 (da)
AT (1) ATE363653T1 (da)
DE (1) DE50210236D1 (da)
DK (1) DK1366352T3 (da)
WO (1) WO2002071043A1 (da)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060197034A1 (en) * 2005-03-04 2006-09-07 Masataka Shirai Counting system for flouescent molecules
US11402200B2 (en) * 2016-03-09 2022-08-02 Hamamatsu Photonics K.K. Measuring device, observing device and measuring method

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5576195B2 (ja) * 2010-06-30 2014-08-20 株式会社ミツトヨ オートフォーカス装置
JP5721406B2 (ja) * 2010-11-24 2015-05-20 Hoya株式会社 走査型共焦点内視鏡システム

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DE8904152U1 (de) 1989-04-04 1989-08-03 Schönbuch Electronic Hanesch GmbH & Co KG, 7031 Nufringen Vorrichtung zum Abtasten und/oder Prüfen von Körperoberflächen
JPH03248793A (ja) 1990-02-26 1991-11-06 Mitsubishi Electric Corp レーザ加工ヘッド
DE69227902T2 (de) 1991-04-29 1999-06-17 Massachusetts Inst Technology Vorrichtung für optische abbildung und messung
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US6377346B1 (en) * 1998-09-17 2002-04-23 Wallac Oy Sample imaging device
US6813050B2 (en) * 2002-01-18 2004-11-02 Nanguang Chen Rotary mirror array for fast optical tomography

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DE8904152U1 (de) 1989-04-04 1989-08-03 Schönbuch Electronic Hanesch GmbH & Co KG, 7031 Nufringen Vorrichtung zum Abtasten und/oder Prüfen von Körperoberflächen
JPH03248793A (ja) 1990-02-26 1991-11-06 Mitsubishi Electric Corp レーザ加工ヘッド
DE69227902T2 (de) 1991-04-29 1999-06-17 Massachusetts Inst Technology Vorrichtung für optische abbildung und messung
US6236457B1 (en) * 1997-03-07 2001-05-22 Varian Australia Pty. Ltd. Spectroscopic analysis
US6377346B1 (en) * 1998-09-17 2002-04-23 Wallac Oy Sample imaging device
DE19950225A1 (de) 1998-10-24 2000-05-18 Leica Microsystems Anordnung zur optischen Abtastung eines Objekts
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060197034A1 (en) * 2005-03-04 2006-09-07 Masataka Shirai Counting system for flouescent molecules
US7439522B2 (en) * 2005-03-04 2008-10-21 Hitachi High-Technologies Corporation Counting system for fluorescent molecules
US11402200B2 (en) * 2016-03-09 2022-08-02 Hamamatsu Photonics K.K. Measuring device, observing device and measuring method

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JP4391746B2 (ja) 2009-12-24
EP1366352B1 (de) 2007-05-30
WO2002071043A1 (de) 2002-09-12
ATE363653T1 (de) 2007-06-15
US20040238729A1 (en) 2004-12-02
DE50210236D1 (de) 2007-07-12
JP2004528543A (ja) 2004-09-16
DK1366352T3 (da) 2007-10-01
EP1366352A1 (de) 2003-12-03

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